Prevalence and Risk Factors of Wellens Syndrome in Patients with Acute Coronary Syndrome

doi:10.21203/rs.3.rs-3232636/v1

Background

Wellens syndrome complicates acute coronary syndrome and, if unmanaged, can lead to immanent myocardial infarction. This study aimed towards determining the prevalence of Wellens syndrome among acute coronary syndrome patients while focusing on both types and identifying the most associated risk factor, then determining the commonest coronary artery affected in those who fulfilled Wellens syndrome criteria.

Methods

Implementing a descriptive cross sectional hospital based observational study design at Ahmed Gasim Teaching Hospital for Cardiac Surgery and Renal Transplantation in Khartoum North, Sudan, the study was conducted using a non probability convenience sampling of patients fitting the inclusion criteria. Data was collected using closed ended structured questionnaires. Ethical clearance was obtained from relevant authorities. Data analysis was done using descriptive and comparative data analysis with the aid of the SPSS software.

Results

A total of 120 patients were included, 70 males and 50 females, majority in their fifth decade. 14 patients had no documented risk factors. 42.5% had STEMI, 34.2% had NSTEMI and 23.3% had unstable angina. Patients fulfilling Wellens syndrome criteria were 18 (15%), 44.4% of them were type A and 55.6 were type B. Specific prevalence among NSTEMI alone was 29.3% and 21.4% among unstable angina alone. Most frequently encountered risk factor among Wellens syndrome patients was Diabetes (50%). Out of 16 Wellens syndrome patients who underwent coronary angiography, 50% had mid LAD involvement, most were of type B; 25% had proximal LAD involvement and 25% had normal coronary angiography. There was significant association between Wellens syndrome and NSTEMI, but no significant association with any specific risk factor.

Conclusion

Wellens syndrome is not a rare condition although uncommon, it can present even without a specific predisposing risk factor and coronary angiographic variation other than the proximal part of the LAD artery may occur.

Wellens Syndrome

Acute Coronary Syndrome

proximal LAD

Biphasic t wave

NSTEMI

coronary angiography

Wellens syndrome was first described in 1982 by Wellens, H J and others(1), as a characteristic electrocardiographic pattern indicating a critical stenosis high in the left anterior descending coronary artery (LAD), which is at high risk for the development of an extensive anterior wall myocardial infarction if left untreated. This specific pattern was later found to be prevalent in about 14% to 18% of patients presenting with acute coronary syndrome and represents both a sensitive and a highly specific indicator for significant proximal left anterior descending artery (LAD) stenosis(2). Although several cases were found to have other coronary arteries alongside or other than the LAD(3), with variation on the associated number of vessels affected(4), while others showed mildly affected LAD suggesting arterial spasm(5). Those cases varied in different studies.

There are two types of Wellens syndrome based on the electrocardiographic (ECG) finding with the first type being the most common(6):

Type A Deeply inverted T-waves in the pericordial leads V2 and V3 Type B biphasic T-waves in the pericordial leads V2 and V3

The following are the required criteria for the diagnose of Wellens syndrome(6,7): Prior history of chest pain.

During chest pain: ECG is normal or with mild ST elevation or depression, or with terminal negative deflection of the T wave in V₁ and V₂.

Cardiac enzymes are normal or mildly elevated. No pathologic precordial Q-waves.

No loss of precordial R-waves.

Deeply inverted or biphasic T-waves in V2 and V3, possibly V1, V4, V5 and/or V6 when pain free(8).

The challenge in diagnosing this syndrome is that it occurs namely during chest pain free periods. However, some cases were encountered without history of chest pain(9), though a case was reported presenting within the initial chest pain period(10).

Since Wellens syndrome is considered a subcategory of acute coronary syndrome, risk factors for its development are equivalent to those of coronary artery disease(11). They include hypertension, diabetes, hyperlipidemia, previous coronary artery events, cigarette smoking, hormone replacement therapy, chronic kidney disease(12,13), family history and even genetic predisposition(14). These risk factors vary in different populations with cigarette smoking being in the lead.

This study focuses on the prevalence of Wellens syndrome among acute coronary syndrome patients, while trying to identify the most prevalently associated predisposing risk factors.

Wellens syndrome is a serious condition that in most cases needs revascularization(8), and can progress rapidly in a matter of a few days, or less, to imminent myocardial infarction(15). Delayed intervention during this narrow window can have fatal, yet predictable, consequences(16). Unfortunately it is often overlooked(17). Therefore, it is essential to study this syndrome in order to ensure effective prevention and proper management.

Most of health care professionals, including junior doctors, can usually identify patients with acute coronary syndrome. Yet Wellens syndrome is under recognized. Therefore, studying its prevalence can help draw more attention to this serious condition. As well as raising awareness to encourage early identification.

Furthermore, among all the internationally published studies found, only few stratified the association of risk factors to the syndrome(18). And knowledge of risk factors variation in different populations is essential for implementation of preventive measures.

Objectives:

General objective:

To determine the prevalence and risk factors of Wellens syndrome in patients with acute coronary syndrome

Specific objectives:

To determine the prevalence of Wellens syndrome in patients with acute coronary syndrome.
To identify the most common type of Wellens syndrome.
To determine the most associated risk factor with Wellens syndrome.

To identify the commonest coronary artery affected in patients with Wellens syndrome.

Wellens syndrome was first described in 1982(1). It revealed characteristic electrocardiographic pattern indicating a critical stenosis high in left anterior descending coronary artery (LAD) in patients admitted because of impending myocardial infarction. These patients, who showed characteristic ST-T segment changes in the precordial leads on or shortly after admission, had critical stenosis high in the LAD. Of the patients consecutively admitted because of unstable angina, 18% showing this ECG pattern, suggesting that this finding is not rare. In spite of symptom control by nitroglycerin and beta blockade, 75% of patients, who were not operated on, developed a usually extensive anterior wall infarction within a few weeks after admission. In view of these observations, they concluded that urgent coronary angiography and, when possible, coronary revascularization should be done in patients with unstable angina who show this ECG pattern.

The development of new T-wave inversion in patients with unstable angina was reported in 1983(15). The electrocardiograms of the patients during hospitalization in the coronary care unit were analyzed for occurrence of new T-wave inversion greater than or equal to 2 mm and correlated with findings at coronary angiography (73 patients) and at follow-up (112 patients). 29 patients had anterior T-wave inversion. Of these, 86% of patients had greater than or equal to 70% diameter reduction of the LAD), compared with 26% of patients without anterior T-wave inversion. The sensitivity of T-wave inversion for significant LAD stenosis was 69%, specificity 89%. The study concluded that development of new T- wave inversion greater than or equal to 2 mm in patients with unstable angina is predictive of significant coronary artery stenosis, and identifies a subgroup with poor prognosis if treated medically.

A larger scale study in 1989(2) revealed that 180 (14%) of 1260 patients consecutively admitted to the hospital because of unstable angina pectoris had the typical ST-T segment changes suggestive of a critical stenosis in the proximal LAD. In 108 patients the ECG abnormalities were present at the time of admission. In the remaining 72 patients they developed shortly thereafter. The difference between these two groups was a longer duration of anginal complaints in the former (mean 2.3 days). Results of coronary angiography, performed a mean of 4.6 days after the last attack of chest pain, showed 50% or more narrowing in the proximal LAD in all patients. 33 patients had complete occlusion of the LAD, and 75 had collateral circulation to the LAD. 15 patients (9 before and 6 during early revascularization) had an anterior wall myocardial infarction in the hospital; these patients had a patent but severely narrowed LAD and a low incidence of collateral circulation to the LAD.

A paper was published describing Wellens syndrome as a pattern of electrocardiographic T-wave changes associated with critical proximal LAD(7). It described Wellens syndrome as a pattern of electrocardiographic T-wave changes associated with critical proximal LAD. The syndrome was also referred to as LAD coronary T-wave syndrome. It also described the syndrome's criteria including T-wave changes plus a history of anginal chest pain without serum marker abnormalities, patients lack Q waves and significant ST-segment elevation and show normal precordial R-wave progression. And emphasizing the natural fate of Wellens syndrome being anterior wall acute myocardial infarction. It also mentioned that the T-wave abnormalities are persistent and may remain in place for hours to weeks; the clinician likely will encounter these changes in the sensation- free patient. With definitive management of the stenosis, the changes resolve with normalization of the electrocardiogram. It is vital that the physician recognize these changes and the association with critical LAD obstruction and significant risk for anterior wall myocardial infarction.

An interesting study was published in Pakistan(4) describing the coronary angiographic findings in patients with unstable angina showing biphasic inversion of T-waves in precordial leads on electrocardiogram, in 100 patients showing the characteristic electrocardiogram pattern. Its Angiographic findings revealed that 50 (50%) patients had coronary artery stenosis in the proximal part of the left anterior descending artery, while 22 (22%) showed the occlusion in the middle segment. And two vessel disease was most commonly observed during cardiac catheterisation.

Another smaller study was published in India(18), taking into consideration risk factors variation, included a total of 40 patients out of which 30 (75%) were male. Their mean age ±SD was 53±10.8years. 25% patients suffered from hypertension, 37.5% had diabetes mellitus, 50% had dyslipidemia, 35% were smokers and 32.5% had history for premature coronary artery disease. On angiographic analysis 35patients (87.5%) had single vessel disease (SVD), 2 patients (5%) had double vessel disease (DVD), and 3 patients (7.5%) had normal coronary arteries. Out of 37 patients the involvement of left anterior descending artery (LAD) was seen in all patients, and 2 patients had circumflex in addition to LAD.

In view of prevalence of Wellens syndrome among acute coronary syndrome patients, a recently published article(3) aimed to study its prevalence, clinical significance and prognostic value in patients with non-ST elevation myocardial infarction (NSTEMI). It was a retrospective analysis of 481 consecutive patients presenting with NSTEMI who underwent coronary angiography within five days after presentation, with exclusion of patients with complete bundle branch block and ventricular paced rhythm. Electrocardiograms were interpreted in a blinded fashion. Patients were categorized into a Wellens group and control group. Baseline and angiographic characteristics in-hospital and 30-day major adverse cardiac event (MACE) including death, recurrent myocardial infarction, and target vessel revascularization were compared between the two groups. Among 424 patients included in the final analysis, 18 patients (4.2%) had Wellens syndrome. Among those 18 patients, 9 had a LAD culprit lesion (3 proximal, 5 mid, and 1 distal LAD), 2 had a non-LAD culprit lesion, and 4 patients had non obstructive coronary artery disease. At the 30-day follow-up, no significant difference was found in the rate of MACE between the two groups. This indicated that Wellens syndrome did not have a short term prognostic value among patients with NSTEMI.

Several case reports were published over the past few years describing typical and atypical presentations. With different types of the syndrome(19). Some described typical cases of young male patients(6,20).

While others described atypical cases such as patient presenting with syncope without chest pain(9). And a reported case of Wellens syndrome in a patient with cocaine abuse with a coronary angiogram showing focal coronary artery vasospasm(21).

A case of a patient's coronary angiography revealed moderate stenosis in proximal LAD, and coronary artery spasm was suggested(5). Also in another case unlike the classic Wellens syndrome, which needs aggressive coronary intervention, the patient showed favorable prognosis with conservative medical therapy(22).

While in a case a patient with previous chest pain, whose ECG showing subtle ischemic changes, was initially overlooked(23). But a repeat ECG taken during the painless period showed a biphasic T wave, suggestive of Wellens syndrome, which was followed by an immediate coronary angiogram.

Other cases reported highlighted associated risk factors such as smoking , diabetes or previous history of coronary artery disease, and named the syndrome 'the widow maker'(17,24).

The youngest reported case of Wellens syndrome(25) was a 24 years old female, who was initially unrecognized and progressed to non ST elevation myocardial infarction (NSTEMI). The patient was found to have critical narrowing of the proximal LAD which was successfully treated with a drug eluting stent. The syndrome was reported occurring in an elderly patient as well(26).

Wellens syndrome has also been identified in a patient with a small plaque in the proximal LAD, with slow flow in the LAD detected by coronary angiography suggesting arterial spasm(5).

In regards to risk factors to developing acute coronary syndrome, which includes Wellens syndrome, in 1984 the Multiple Risk Factor Intervention Trial screening program(27) provided an opportunity to study the association of diastolic blood pressure level, serum cholesterol concentration, and cigarettes per day with all-cause and cause-specific mortality, including coronary heart disease (CHD) and cerebrovascular disease mortality, after 5 years among 23,490 black males and to compare these associations with those observed among 325,384 white males. The relationship of serum cholesterol concentration and reported cigarettes per day to all-cause, coronary heart disease (CHD), and cerebrovascular disease mortality was similar for black and white males, and the lower coronary heart disease mortality among black males compared to white males was most apparent among hypertensive males.

Later, a multinational study took place in 2005(11) involving 103 hospitals in 25 countries in Europe and the Mediterranean basin. The study included 10,253 patients with a discharge diagnosis of acute coronary syndrome (ACS). Revealing that patients with ACS who were smokers had an increased risk to present with ST elevation. Hypertension and high body mass index (BMI) were associated with less ST elevation ACS. Diabetes mellitus was also associated with less ST elevation, but only among men. Prior disease (infarction, and revascularization) and treatment with aspirin, beta blockers, or statins before admission were also associated with less ST elevation. After adjustment for age, sex, prior disease and prior medication, smoking was still significantly associated with increased risk of ST elevation. Whereas hypertension was associated with reduced risk. Obesity (BMI > 30 kg/m2 versus < 25 kg/m2) was independently associated with less risk of presenting with ST elevation among women, but not among men.

This study aimed towards determining the prevalence of Wellens syndrome among patients with acute coronary syndrome while focusing on both syndrome types and identifying the most associated risk factor, then determining the commonest coronary artery affected in those who fulfilled the criteria for Wellens syndrome.

Results were obtained through the final analysis of 120 patients who fit the inclusion criteria of the study, taking into account the demographical distribution of data as well as the objectives of the study.

There were no missing data in regards to study variables.

Demographics:

Out of the 120 patients, 70 (57.3%) were males and 50 (41.7%) were females (Table 1). The majority of patients were in their fifth decade (25.8% in the range of 50-59 years), followed closely by the seventh decade (25% in the range of 70-79 years) (Table 2) (Figure 1).

Risk factors:

The majority of patients (106, 88.3%) had risk factors for the development of acute coronary syndrome, and only 14 patients (11.7%) had no documented risk factors with the exclusion of age and gender variation (Table 3). The commonest risk factor was hypertension (45.8%), followed closely by diabetes (45.0%). The least prevalent risk factor was chronic kidney disease (one patient, 0.8%). Relevant to mention that total number of cigarette smoking patients were 27 (22.5%), most (92.6%) of which were males with a statistically significant association (Pearson Chi-Square 16.8, p-value <0.01) (Table 4). Other risk factors varied (Figure 2, 3, 4, 5, 6, 7, 8).

Types of acute coronary syndrome:

All 120 patients fulfilled the inclusion criteria and were diagnosed with acute coronary syndrome. 51 of the patients (42.5%) were diagnosed with ST elevation myocardial infarction (STEMI), while 41 (34.2%) where cases of none ST elevation myocardial infarction (NSTEMI), and the rest (28, 23%) were unstable angina patients. (Table 5)

Prevalence of Wellens syndrome:

The total number of patients fulfilling the criteria of Wellens syndrome was 18 patients (15%) (Table 6), 8 of which (44.4%) were type A (T wave inversion in V2-V3), and 10 (55.6%) were type B (biphasic T waves in V2-V3T) (Table 7).

Out of the 18 Wellens syndrome patients, 12 (66.7%) of them were diagnosed as NSTEMI, the rest (6, 33.3%) were unstable angina patients. (Table no. 8).

None of the STEMI patients fulfilled Wellens syndrome criteria, though 4 STEMI patients fulfilled all criteria except the presence of Q wave on their obtained ECG, thus excluding Wellens syndrome.

The 12 NSTEMI patients who fulfilled Wellens syndrome criteria represented 29.3% out of the total NSTEMI patient in the total population, while the 8 unstable angina patients represented 21.4% (Pearson Chi-Square 16.454, P-value <0.01). (Table 8).

Type of Wellens syndrome:

Among patients who were type A Wellens syndrome (8 patients), 6 were NSTEMI patients (75%) and 2 were unstable angina patients (25%). On the other hand, among the 10 type B patients, 6 were NSTEMI patients (60%) and 4 were unstable angina patients (40%) (Pearson Chi-Square 0.45, P-value 0.5). (Table 9).

Risk factors of Wellens syndrome:

Out of the 18 Wellens syndrome patients, there were 2 patients who had no identifiable risk factor for the development of acute coronary syndrome.

Among Wellens syndrome patients who had documented risk factors , 9 (56.3%) were diabetics, 7 (43.8%) had hypertension, 5 (31.3%) had family history of coronary artery

disease, 3 (18.8%) had Hyperlipidemia, 3 (18.8%) were smokers and only 1 (6.3%) had previous history of coronary artery disease as well as one patient (6.3%) had chronic kidney disease (Table 10).

6 Wellens syndrome patients were in their sixth decade, representing the highest frequency (33.3%) of total Wellens syndrome patients, and one patient was in the second decade representing the lowest. None of Wellens syndrome patients were in their third decade. (Pearson Chi-Square 3.06, P-value 0.69). (Table 11).

The majority of Wellens syndrome patients were males, representing 61.1% (11 patients). Female patients represented 38.9% (7 patients). (Pearson Chi-Square 0.067, P-value 0.795). (Table 12).

The most frequent risk factor was diabetes, representing 50% of Wellens syndrome patients. (Pearson Chi-Square 0.21, P-value 0.64) (Table 13). The least frequent risk factors were previous coronary artery disease and chronic kidney disease; each was present in only one patient.

Affected coronary arteries:

Coronary angiographic findings were followed in all patients who fulfilled Wellens syndrome criteria. It is Relevant to mention that 2 out of the total 18 Wellens syndrome patients did not undergo coronary angiography. One of the two had difficulty in arterial line cannulation and was referred to another center outside the study area. The other patient was young and had no identifiable risk factor for coronary artery disease, and was recommended for none invasive approach after risk stratification. Both were excluded from data analysis in regards to angiographic findings.

Among the 16 Wellens syndrome patients who underwent coronary angiography, half (8, 50%) had an affected Mid left anterior descending artery, 4 (25%) had proximal LAD artery involvement, 4 (25%) had none isolated right coronary artery involvement, 4 (25%) had normal coronary angiography, 3 (18%) had left circumflex artery involvement, one patient (6.3%) had an affected left main coronary artery and one patient (6.3%) had diagonal artery involvement. (Table 14).

None of Wellens syndrome patients had distal left anterior descending artery involvement.

Out of the 10 type B Wellens syndrome patients who underwent coronary angiography, 6 had mid LAD involvement representing the majority of (60%) of that type. And 2 patients (20%) had proximal LAD artery involvement. While in type A Wellens syndrome patients, both proximal and mid LAD artery were affected in 2 patients respectively, each representing 33.3% of all type A patients. (Table 15).

This descriptive cross sectional study provided supportive evidence to more enlightenment about Wellens syndrome with special regards to its prevalence, risk factors and potential variation in coronary angiographic findings.

Studying of Wellens syndrome risk factors and angiographic findings was reinforced by the acceptable prevalence which was encountered, though being an uncommon condition may affect the ability of results to represent different populations in general.

Demographics:

Out of the total population fulfilling the inclusion criteria (120 patients), there was no significant variation in regards to gender, though males (57.3%) were slightly more frequent than females. (Table 1).

Descriptive analysis showed that there are two peaks in prevalence of acute coronary syndrome, namely fifth and seventh decades. While seventh decade peak is expected, the fifth decade peak suggests presence of more risk factors that would explain its frequency. (Figure 2).

Risk factors:

Out of the 120 acute coronary patients, only 14 patients had no identifiable risk factor after excluding age and gender. Acute coronary syndrome in many cases was reported in patients with no known risk factors.

The commonest two risk factors encountered were Hypertension (45.8%) and Diabetes (45%), with Hypertension being slightly more frequent. Smoking represented only (22.5%). And there was only one patient who had chronic kidney disease (Figure 2, 3, 4, 5, 6, 7, 8). These finding slightly deviate from the multinational study(11) that highlighted smoking as the most associated risk for acute coronary syndrome especially STEMI. It is acceptable to suggest that prevalence of both diabetes and hypertension is higher than smokers who are complicated by acute coronary syndrome in the study population.

Also the gender distribution among smokers showed that there is significant variation suggesting that males are more associated with cigarette smoking than females (p-value

<0.01). This would contribute to the lower incidence of acute coronary syndrome specifically due to smoking among females.

Types of acute coronary syndrome:

Most of the patients were diagnosed with STEMI (42.5%), while NTSEMI and unstable angina represent 34.2% and 23.3% respectively (Table 5).

Prevalence of Wellens syndrome:

The study revealed that the overall prevalence of Wellens syndrome among acute coronary syndrome is 15% regardless of acute coronary syndrome type (Table 7). Thus answering one of the main study questions. This finding is similar to previous studies that found a prevalence of 14% and 18% in different populations (1,2). However, those studies had an inclusion criteria of unstable angina only. Similarly, the recently published article(3) found a prevalence of 4.2% but among NSTEMI patient alone.

Further analysis revealed a prevalence with cross tabulation for each type of acute coronary syndrome. The NSTEMI Wellens syndrome patients constituted 29.3% of the total NSTEMI patients. While the unstable angina Wellens syndrome patients constituted 21.4% of the total unstable angina patients. (Pearson Chi-Square 16.454, P-value <0.01). Which suggests that Wellens syndrome is more associated with NSTEMI, and its frequency is not rare.

None of the STEMI patients fulfilled Wellens syndrome criteria. This supports previous evidence that Wellens syndrome occurs mainly in NSTEMI and unstable angina. Interestingly enough, 4 STEMI patient fulfilled all Wellens syndrome criteria except for the presence of Q waves. Following their coronary angiographic findings out of interest revealed proximal LAD involvement in all 4, which is the classical finding originally described(1). Even thought they are not considered Wellens syndrome patients.

Type of Wellens syndrome:

Analysis of the 18 Wellens syndrome patients revealed that 44.4% were type A and 55.6% were type B, the later being more frequent. Furthermore, cross tabulation of Wellens syndrome types with acute coronary syndrome types showed that NSTEMI is the most associated acute coronary syndrome with both type A as well as type B, representing 75% and 60% respectively. In spite of that, statistical analysis suggests that this association is not strongly significant (p-value >0.05).

Risk factors of Wellens syndrome:

Despite having no identifiable risk factors, 2 out of the 18 Wellens syndrome patients developed acute coronary syndrome and fulfilled Wellens syndrome criteria (Table 10), suggesting that Wellens syndrome can occur, though uncommon, without apparent risk factors resembling acute coronary syndrome in that manner.

Further analysis revealed that the most frequently encountered risk factors among Wellens syndrome patients were Diabetes (56.3%) and Hypertension (43.8%), with the former being more frequent(Table 13). This supports a few case report with Wellens syndrome patient being diabetics(17,24). But deviates from a recent study that highlighted Hyperlipidemia as the most frequently encountered risk factor in Wellens syndrome. This may be due to variation of acute coronary syndrome risk factor profiles in different populations. Specific cross tabulation for Diabetes with the total number of Wellens syndrome patients revealed that 50% of the total Wellens syndrome patients were diabetics. Despite of that, analysis suggests that the association is not strongly significant (p-value>0.05).

Similar Analysis showed that there is no statistically significant association between Wellens syndrome and age or gender of the patient, despite sixth decade (33.3%) and male gender (61.1%) being most frequently encountered.

Affected coronary arteries:

After excluding the 2 patients who had no coronary angiographic data, descriptive analysis was done to the remaining 16 patients. The most frequently affected coronary artery part was the mid LAD artery, representing 50% of those patients. Proximal LAD artery involvement was present in only 25% of the patients. This deviated from the classical finding in previous studies that suggests proximal LAD involvement as the most common (1,2,4,15,18), in spite of being the same artery. Relevant to mention that mid LAD artery involvement was encountered in a previous study as well (4).

It is important to mention that 25% of Wellens syndrome patient had normal coronary angiography (Table 14). This supports previous finding in that not all patients who fulfill Wellens syndrome criteria have coronary artery disease(18). And Wellens syndrome though highly specific, specificity does not reach 100%(15).

60% of type B of Wellens syndrome patient had mid LAD involvement. Although there is no statistically significant association between Wellens syndrome type and acute coronary syndrome (Table 15), this finding may suggest that mid LAD involvement can be encountered in type B Wellens syndrome more than type A, though not statistically significant. Type A Wellens syndrome patient had no predominantly frequent coronary artery affected. None of the studies in the literature review had results describing association of Wellens syndrome type with coronary angiographic findings.

Despite being relatively uncommon, Wellens syndrome is a serious condition that is not classified as a rare complication. It can be encountered in any acute coronary syndrome patient with the exclusion of STEMI, either NSTEMI or unstable angina, and being more prevalent in NSTEMI patients. Type B Wellens syndrome can be encountered more frequently than type A.

Wellens syndrome can complicate acute coronary syndrome even without identifiable risk factors. Diabetes was the most frequently encountered risk factor in Wellens syndrome patients. However, no specific risk factor had statistically significant association.

Coronary angiographic findings other than the involvement of the proximal part of the left anterior descending artery can present. The most frequently encountered in this study was the mid part of the left anterior descending artery. However, it is possible for patients who fulfill Wellens syndrome criteria to have a normal coronary angiography regardless of Wellens syndrome type and presence of risk factors.

Study design:

This was a descriptive cross sectional hospital based observational study.

Study area:

Ahmed Gasim Teaching Hospital for Cardiac Surgery and Renal Transplantation, Khartoum North, Sudan.

Study population:

The study population included all patients in view of the case definition, inclusion and exclusion criteria.

Case definition:

Any adult patient of any gender who presented to the study area and is diagnosed with acute coronary syndrome of any type.

Inclusion criteria:

Any patient according to the case definition.

Exclusion criteria:

Any patient where data about their risk factors were unable to be obtained or is incomplete.

Any patient who did not have an electrocardiogram (ECG) recorded during a pain free

period.

Any patient who was unable to provide an informed consent.

Sampling:

The study was conducted using a non probability convenience sampling, using total coverage of any patient who fit the inclusion criteria inside the study area, during the period between April 2017 and September 2017.

Data collection methods and tools:

Data was collected using closed ended structured questionnaires filled by previously taught and trained data collectors, who are medical doctors capable of identifying the patients according the case definition. Wellens syndrome criteria was obtained from the patient's electrocardiogram (ECG) done in chest pain free periods. All ECGs done for patients with acute coronary syndrome was observed during the period of hospital stay. Clinical data regarding risk factors was taken from the patient through short interviews and with the use of confirmed clinical records or laboratory investigations as appropriate. Coronary angiographic data, if present, was obtained from direct observation of the procedure with the aid of the operating cardiologist, or through a coronary angiography report performed and signed by a cardiologist.

Data management:

Data were revised, coded and sorted into a master sheet. According the study variables and with the aid of an approved statistician, descriptive data analysis was done using the mean, median, standard deviations, tables, charts and frequency distribution. As well as comparative statistics using cross tabulations, Chi square testing and p value calculation. The SPSS software was used as a data management and analysis tool

Limitations:

This descriptive cross sectional study was conducted in one cardiac centre that,

despite being a highly selective center of referral for many state hospitals, limits the number of encountered patients who fulfilled the inclusion criteria. Also important to mention that extending the period as well as expanding study area, and sample size, with supported facilitation would relieve some limitations that might have anckered producing more statistically significant results, taking into account the limited numbers of patients who fulfilled Wellens syndrome criteria.

Recommendations:

Awareness should be raised towards early identification of Wellens syndrome by practicing physicians and health care providers in order to reduce the number of missed cases and thus preventing the development of irreversible consequences.

It is acceptable to mention that, given the proven prevalence in this as well as previous studies, further studies of Wellens syndrome should focus on the condition as inclusion criteria of research. This would allow more in depth analysis of its pattern of incidence. A larger sample size might need a more prolonged period of time to attain an acceptable representation of any given population, but would ultimately produce statistically significant results that can help in answering questions this study could not.

Results of this study suggest that Wellens syndrome does not have a specific risk factor pattern for prediction despite finding risks more frequent than others. However, given its limitations it is safe to recommend that a more focused approach to Wellens syndrome risk factors should be implemented taking into account population variation of acute coronary syndrome risk factors.

Reasons behind coronary angiographic variation in Wellens syndrome could not be explained well despite being in line with previous findings of specificity. Therefore, inclusion of Wellens syndrome type variation beside coronary angiographic findings on a larger scale may help define pattern of presentation.

ACS:Acute coronary syndrome, DM: Diabetes Mellitus, ECG:Electrocardiogram, LAD:Left anterior descending, LCx:Left circumflex, MACE:Major adverse cardiac event, NSTEMI:None ST elevation myocardial infarction, RCA:Right coronary artery, SPSS:Statistical package for the social sciences, STEMI:ST elevation myocardial infarction

Ethical Approval:

Ethical clearance was obtained from authorities namely the Sudan Medical Specialization Board (SMSB), and the study area as appropriate. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Consent to participate:

An informed verbal consent was obtained from each patient before data collection while ensuring clear confidentiality and anonymity during data collection from both patients and collectors.

Consent for publication:

Informed verbal consent was obtained from each patient for publication of this study.

Availability of data and materials:

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests:

The authors declare that they have no competing interests.

Funding:

There were no funding nor grants.

Authors' contributions:

SM. contributions: conceptualization, literature search, methodology, investigation, data curation, formal analysis, manuscript writing, review, editing and validation.

SA. contributions: project administration, supervision, literature review, visualization, investigation, case validation and manuscript review.

Acknowledgments:

Appreciations to support from Ahmed Gasim teaching hospital’s administration, staff, cardiology department and all fellow colleagues in addition to Sudan Medical Specialization Board for providing grounds for the opportunity.

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Table no.1 Gender distribution of patients with percentages of total population

Frequency			Percent	Valid Percent
Valid	Male	70	58.3	58.3
	Female	50	41.7	41.7
	Total	120	100.0	100.0

Out of the 120 patients, 70 (57.3%) were males and 50 (41.7%) were females

Table no.2 Age distribution of patients with and percentages of total population

Frequency			Percent	Valid Percent
Valid	20-29 years	3	2.5	2.5
	30-39 years	5	4.2	4.2
	40-49 years	22	18.3	18.3
	50-59 yeas	31	25.8	25.8
	60-69 years	29	24.2	24.2
	70-79 years	30	25.0	25.0
	Total	120	100.0	100.0

The majority of patients were in their fifth decade (25.8% in the range of 50-59 years), followed closely by the seventh decade (25% in the range of 70-79 years)

Table no.3 Risk factors for acute coronary syndrome with percentages of total population

Present			Missing		Total
N		Percent	N	Percent	N	Percent
Risk factors	106	88.3%	14	11.7%	120	100.0%
No of patients					Percent
Risk factors	Hypertension		55		45.8%
	Diabetes		54		45.0%
	Hyperlipidemia		17		14.2%
	Family history of coronary artery disease		37		30.8%
	Previous coronary artery disease		16		13.3%
	Chronic kidney disease		1		0.8%
	Smoking		27		22.5%

The majority of patients (106, 88.3%) had risk factors for the development of acute coronary syndrome, and only 14 patients (11.7%) had none

Table no.4 Gender distribution of cigarette smoking patient

Gender					Total
Male				Female	Total
Smoking	Yes	Count	25	2	27
		Expected Count	15.8	11.3	27.0
		% within Smoking	92.6%	7.4%	100.0%
Pearson Chi-Square			Value	df	Asymptotic Significance (2-sided)
Pearson Chi-Square			16.823^a	1	.000

total number of cigarette smoking patients were 27 (22.5%), most (92.6%) of which were males

Table no.5 Type of acute coronary syndrome percentages of total population

Frequency			Percent	Valid Percent
Valid	STEMI	51	42.5	42.5
	NSTEMI	41	34.2	34.2
	Unstable angina	28	23.3	23.3
	Total	120	100.0	100.0

51 of the patients (42.5%) were diagnosed with ST elevation myocardial infarction (STEMI), while 41 (34.2%) where cases of none ST elevation myocardial infarction (NSTEMI), and the rest (28, 23%) were unstable angina patients

Table no.6 Number and percentage of patients fulfilling criteria for Wellens syndrome of total population

Frequency			Percent	Valid Percent
Wellens syndrome criteria fulfilled	Yes	18	15.0	15.0
	No	102	85.0	85.0
	Total	120	100.0	100.0

The total number of patients fulfilling the criteria of Wellens syndrome was 18 patients (15%)

Table no.7 Type of Wellens syndrome percentages of total population

Frequency			Percent	Valid Percent
Type of Wellens syndrome	Type A (inverted T wave in V2-V3)	8	6.7	44.4
	Type B (biphasic T wave in V2-V3)	10	8.3	55.6
	Total	18	15.0	100.0
Patients not fulfilling Wellens syndrome criteria		102	85.0
Total		120	100.0

The total number of patients fulfilling the criteria of Wellens syndrome was 18 patients (15%), 8 of which (44.4%) were type A (T wave inversion in V2-V3), and 10 (55.6%) were type B (biphasic T waves in V2-V3T)

Table no.10 Risk factors / Wellens syndrome cross tabulation

			Wellens syndrome criteria fulfilled		Total
			Yes	No	Total
Risk factors	Hypertension	Count	7	48	55
	Hypertension	% within Wellens_syndrome_criteria_fulfilled	43.8%	53.3%
	Diabetes	Count	9	45	54
	Diabetes	% within Wellens_syndrome_criteria_fulfilled	56.3%	50.0%
	Hyperlipidemia	Count	3	14	17
	Hyperlipidemia	% within Wellens_syndrome_criteria_fulfilled	18.8%	15.6%
	Family history of coronary artery disease	Count	5	32	37
	Family history of coronary artery disease	% within Wellens_syndrome_criteria_fulfilled	31.3%	35.6%
	Previous coronary artery disease	Count	1	15	16
	Previous coronary artery disease	% within Wellens_syndrome_criteria_fulfilled	6.3%	16.7%
	Chronic kidney disease	Count	1	0	1
	Chronic kidney disease	% within Wellens_syndrome_criteria_fulfilled	6.3%	0.0%
	Smoking	Count	3	24	27
	Smoking	% within Wellens_syndrome_criteria_fulfilled	18.8%	26.7%
Total		Count	16	90	106

Among Wellens syndrome patients who had documented risk factors , 9 (56.3%) were diabetics, 7 (43.8%) had hypertension, 5 (31.3%) had family history of coronary artery

disease, 3 (18.8%) had Hyperlipidemia, 3 (18.8%) were smokers and only 1 (6.3%) had previous history of coronary artery disease as well as one patient (6.3%) had chronic kidney disease

Table no.14 Affected coronary arteries / Wellens syndrome cross tabulation

			Wellens syndrome criteria fulfilled	Total
			Yes	Total
Affected coronary artery	Normal coronary arteries	Count	4	4
	Normal coronary arteries	% within Wellens_syndrome_criteria_fulfilled	25.0%
	Left main coronary artery	Count	1	1
	Left main coronary artery	% within Wellens_syndrome_criteria_fulfilled	6.3%
	Proximal left anterior descending artery	Count	4	4
	Proximal left anterior descending artery	% within Wellens_syndrome_criteria_fulfilled	25.0%
	Mid left anterior descending artery	Count	8	8
	Mid left anterior descending artery	% within Wellens_syndrome_criteria_fulfilled	50.0%
	Diagonal artery	Count	1	1
	Diagonal artery	% within Wellens_syndrome_criteria_fulfilled	6.3%
	Left circumflex artery	Count	3	3
	Left circumflex artery	% within Wellens_syndrome_criteria_fulfilled	18.8%
	Right coronary artery	Count	4	4
	Right coronary artery	% within Wellens_syndrome_criteria_fulfilled	25.0%
Total		Count	16	16

Among the 16 Wellens syndrome patients who underwent coronary angiography, half (8, 50%) had an affected Mid left anterior descending artery, 4 (25%) had proximal LAD artery involvement, 4 (25%) had none isolated right coronary artery involvement, 4 (25%) had normal coronary angiography, 3 (18%) had left circumflex artery involvement, one patient (6.3%) had an affected left main coronary artery and one patient (6.3%) had diagonal artery involvement

Table no.15 Coronary artery affected / Wellens syndrome type cross tabulation

			Type A (inverted T wave in V2-V3)	Type B (biphasic T wave in V2- V3)
Affected coronary artery	Normal coronary arteries	Count	2	2	4
	Normal coronary arteries	% within Type_of_Wellens	33.3%	20.0%
	Left main coronary artery	Count	0	1	1
	Left main coronary artery	% within Type_of_Wellens	0.0%	10.0%
	Proximal left anterior descending artery	Count	2	2	4
	Proximal left anterior descending artery	% within Type_of_Wellens	33.3%	20.0%
	Mid left anterior descending artery	Count	2	6	8
	Mid left anterior descending artery	% within Type_of_Wellens	33.3%	60.0%
	Diagonal artery	Count	0	1	1
	Diagonal artery	% within Type_of_Wellens	0.0%	10.0%
	Left circumflex artery	Count	1	2	3
	Left circumflex artery	% within Type_of_Wellens	16.7%	20.0%
	Right coronary artery	Count	1	3	4
	Right coronary artery	% within Type_of_Wellens_syndrome	16.7%	30.0%
Total		Count	6	10	16

Out of the 10 type B Wellens syndrome patients who underwent coronary angiography, 6 had mid LAD involvement representing the majority of (60%) of that type. And 2 patients (20%) had proximal LAD artery involvement. While in type A Wellens syndrome patients, both proximal and mid LAD artery were affected in 2 patients respectively, each representing 33.3% of all type A patients.

Tables 8, 9, 11, 12, and 13 are available in the Supplementary Files section.

No competing interests reported.

Tables89111213.docx

Prevalence and Risk Factors of Wellens Syndrome in Patients with Acute Coronary Syndrome

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Abstract

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Literature review

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Abbreviations

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